Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

BACKGROUND: The role of conversion surgery in patients with unresectable biliary tract cancer (BTC) who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. METHODS: In this cohort study, patients with advanced BTC who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. RESULTS: Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months post-initiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (non-surgical group). The median interval from the initial antitumor therapy to surgery was 6.7 (interquartile range [IQR] 4.9-9.2) months. Survival with conversion surgery was significantly longer than the non-surgical cohort, with a median progression-free survival (PFS) (unreached vs. 12.4 mo; hazard ratio 0.17 [95% CI 0.06-0.48]; P=0.001) and overall survival (OS) (unreached vs. 22.4 mo; hazard ratio 0.28 [95% CI 0.09-0.84]; P=0.02), respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, 8 patients survived without recurrence. The estimated 3-year OS, PFS and recurrence-free survival rate in the surgical cohort were 59.9%, 59.2% and 60.6%, respectively. The R0 resection rate reached 92.3%, with 2 achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS (P=0.03) and PFS survival (P=0.003). CONCLUSION: Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors (ICIs)-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7.

OBJECTIVE: Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. METHODS AND RESULTS: We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis. CONCLUSION: This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments.

Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.

Identification and validation of the association of Janus kinase 2 mutations with the response to immune checkpoint inhibitor therapy.

BACKGROUND: Janus kinase 2 (JAK2) mutation plays an important role in T cell immunity. However, the effect of JAK2 mutation on immunotherapy is largely uncharacterized. METHODS: In this study, we analyzed the effect of JAK2 mutation on the efficacy and outcomes of immune checkpoint inhibitor (ICI) therapy in the discovery cohort (n = 662) and the verification cohort (n = 1423). Furthermore, we explored the association of JAK2 mutation with the tumor immune microenvironment in a multiomics cohort. RESULTS: In the discovery cohort (n = 662), JAK2 mutant-type patients had a better objective response rate (58.8% vs. 26.7%, P = 0.010), durable clinical benefit (64.7% vs. 38.9%, P = 0.043), progression-free survival (hazard ratio [HR] = 0.431, P = 0.015), and overall survival (HR = 0.378, P = 0.025), relative to JAK2 wild-type patients. Moreover, we further verified the prognostic significance of JAK2 mutation in an independent ICI treatment cohort with a larger sample size (n = 1423). In addition, we discovered that the JAK2 mutation was remarkably related to increased immunogenicity, such as a higher TMB, higher expression of costimulatory molecules and stimulation of antigen processing mechanisms. In addition, JAK2 mutation was positively correlated with activated anticancer immunity, such as infiltration of various immune cells and higher expression of chemokines. CONCLUSION: Our study demonstrates that JAK2 mutation is a novel marker that can be used to effectively predict prognosis and response to ICI therapy.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.

BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

Genomic analysis and filtration of novel prognostic biomarkers based on metabolic and immune subtypes in pancreatic cancer.

PURPOSE: Patients with pancreatic cancer (PC) can be classified into various molecular subtypes and benefit from some precise therapy. Nevertheless, the interaction between metabolic and immune subtypes in the tumor microenvironment (TME) remains unknown. We hope to identify molecular subtypes related to metabolism and immunity in pancreatic cancer METHODS: Unsupervised consensus clustering and ssGSEA analysis were utilized to construct molecular subtypes related to metabolism and immunity. Diverse metabolic and immune subtypes were characterized by distinct prognoses and TME. Afterward, we filtrated the overlapped genes based on the differentially expressed genes (DEGs) between the metabolic and immune subtypes by lasso regression and Cox regression, and used them to build risk score signature which led to PC patients was categorized into high- and low-risk groups. Nomogram were built to predict the survival rates of each PC patient. RT-PCR, in vitro cell proliferation assay, PC organoid, immunohistochemistry staining were used to identify key oncogenes related to PC RESULTS: High-risk patients have a better response for various chemotherapeutic drugs in the Genomics of Drug Sensitivity in Cancer (GDSC) database. We built a nomogram with the risk group, age, and the number of positive lymph nodes to predict the survival rates of each PC patient with average 1-year, 2-year, and 3-year areas under the curve (AUCs) equal to 0.792, 0.752, and 0.751. FAM83A, KLF5, LIPH, MYEOV were up-regulated in the PC cell line and PC tissues. Knockdown of FAM83A, KLF5, LIPH, MYEOV could reduce the proliferation in the PC cell line and PC organoids CONCLUSION: The risk score signature based on the metabolism and immune molecular subtypes can accurately predict the prognosis and guide treatments of PC, meanwhile, the metabolism-immune biomarkers may provide novel target therapy for PC.

Efficacy, safety, and prognostic factors of PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy as first-line treatment in advanced intrahepatic cholangiocarcinoma: a multicenter real-world study.

BACKGROUND: A programmed cell death protein-1 (PD-1) inhibitor combined with lenvatinib and Gemox chemotherapy as first-line therapy demonstrated high anti-tumor activity against biliary tract cancer in phase II clinical trials. Herein, we aimed to investigate the efficacy and safety for advanced intrahepatic cholangiocarcinoma (ICC) in a multicenter real-world study. METHODS: Patients with advanced ICC who received PD-1 inhibitor combined with lenvatinib and Gemox chemotherapy were retrospectively screened at two medical centers. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors for survival were analyzed. RESULTS: Fifty-three patients with advanced ICC were included in this study. The median follow-up time was 13.7 (95% confidence interval (CI): 12.9-17.2) months. The median OS and PFS were 14.3 (95% CI: 11.3-NR) and 8.63 (95% CI: 7.17-11.6) months, respectively. The ORR, DCR, and clinical benefit rate were 52.8, 94.3, and 75.5%, respectively. In the multivariate analysis, the tumor burden score (TBS), tumor-node metastasis classification (TNM) stage, and PD-L1 expression were independent prognostic factors for OS and PFS. All patients experienced adverse events (AEs), 41.5% (22/53) experienced grade 3 or 4 AEs, including fatigue (8/53, 15.1%) and myelosuppression (7/53, 13.2%). No grade 5 AEs were reported. CONCLUSION: PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy represent an effective and tolerable regimen for advanced ICC in a multicenter retrospective real-world study. TBS, TNM stage, and PD-L1 expression can be used as potential prognostic factors for OS and PFS.

Development and validation of a selenium metabolism regulators associated prognostic model for hepatocellular carcinoma.

BACKGROUND: Selenium metabolism has been implicated in human health. This study aimed to identify a selenium metabolism regulator-based prognostic signature for hepatocellular carcinoma (HCC) and validate the role of INMT in HCC. METHODS: Transcriptome sequencing data and clinical information related to selenium metabolism regulators in TCGA liver cancer dataset were analysed. Next, a selenium metabolism model was constructed by multiple machine learning algorithms, including univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. Then, the potential of this model for predicting the immune landscape of different risk groups was evaluated. Finally, INMT expression was examined in different datasets. After knockdown of INMT, cell proliferation and colony formation assays were conducted. RESULTS: A selenium metabolism model containing INMT and SEPSECS was established and shown to be an independent predictor of prognosis. The survival time of low-risk patients was significantly longer than that of high-risk patients. These two groups had different immune environments. In different datasets, including TCGA, GEO, and our PUMCH dataset, INMT was significantly downregulated in HCC tissues. Moreover, knockdown of INMT significantly promoted HCC cell proliferation. CONCLUSIONS: The current study established a risk signature of selenium metabolism regulators for predicting the prognosis of HCC patients. INMT was identified as a biomarker for poor prognosis of HCC.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma.

BACKGROUND: Programmed death receptor-1 (PD-1) inhibitors have been approved as second-line treatment regimen in hepatocellular carcinoma (HCC), but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy. AIM: To estimate the clinical outcome of transarterial chemoembolization (TACE) and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC (uHCC). METHODS: We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022. 45 patients received the PD-1 inhibitors, lenvatinib, TACE (PD-1-Lenv-T) therapy, and 20 received the lenvatinib, TACE (Lenv-T) therapy. In terms of the dose of lenvatinib, 8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg. Of the patients in the PD-1 inhibitor combination group, 15 received Toripalimab, 14 received Toripalimab, 14 received Camrelizumab, 4 received Pembrolizumab, 9 received Sintilimab, and 2 received Nivolumab, 1 with Tislelizumab. According to the investigators' assessment, TACE was performed every 4-6 wk when the patient had good hepatic function (Child-Pugh class A or B) until disease progression occurred. We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors (mRECIST criteria). We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events, v 5.0. The key adverse events (AEs) after the initiation of combination therapy were observed. RESULTS: Patients with uHCC who received PD-1-Lenv-T therapy (n = 45) had a clearly longer overall survival than those who underwent Lenv-T therapy (n = 20, 26.8 vs 14.0 mo; P = 0.027). The median progression-free survival time between the two treatment regimens was also measured {11.7 mo [95% confidence interval (CI): 7.7-15.7] in the PD-1-Lenv-T group vs 8.5 mo (95%CI: 3.0-13.9) in the Lenv-T group (P = 0.028)}. The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4% and 20% (P = 0.059) according to the mRECIST criteria, meanwhile the disease control rates were 93.3% and 64.0% (P = 0.003), respectively. The type and frequency of AEs showed little distinction between patients received the two treatment regimens. CONCLUSION: Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer.

Background: Lenvatinib combined with anti-PD-1 antibodies and systemic chemotherapy has demonstrated a relatively high antitumor activity for intrahepatic cholangiocarcinoma in phase 2 clinical trials. However, its efficacy and safety in advanced biliary tract cancer (BTC) has not been reported in a real-world study. Methods: Patients with advanced BTC who received lenvatinib combined with PD-1/PD-L1 inhibitors plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety were evaluated. Results: Fifty-seven patients with advanced BTC were included in the study. The median follow-up time was 15.1 (95% CI: 13.6-19.7) months. The median overall survival and progression-free survival were 13.4 (95% CI: 10.0-NA), and 9.27 (95% CI: 7.1-11.6) months, respectively. The objective response rate, disease control rate and clinical benefit rate were 43.9% (95% CI: 31.8%-56.7%), 91.2% (95% CI: 81.1%-96.2%), and 73.7% (95% CI: 61.0%-83.4%), respectively. Subgroup analysis revealed that the first-line treatment group had a longer median progression-free survival (12.13 vs. 6.77 months, P<0.01) and median overall survival (25.0 vs. 11.6 months, P=0.029) than the non-first-line treatment group. Moreover, three patients underwent conventional surgery after treatment. All patients (100%) experienced adverse events, and 45.6% (26/57) experienced grade 3 or 4 adverse events. The most commonly observed grade 3 or 4 adverse events was myelosuppression (7/57, 12.3%). No grade 5 adverse events were reported. Conclusion: Lenvatinib combined with PD-1/PD-L1 inhibitors and Gemox chemotherapy represents an effective and tolerable treatment option in patients with advanced BTC.

Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients.

INTRODUCTION: Combining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of un-resectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy of and prognostic factors for survival associated with lenvatinib plus PD-1 inhibitor treatment in a large cohort of Asian uHCC patients even the global LEAP-002 study failed to achieve the primary endpoints. METHODS: Patients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and adverse events (AEs). Prognostic factors for survival were also analyzed. RESULTS: A total of 378 uHCC patients from two medical centers in China were assessed retrospectively. The median patient age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant etiology of uHCC. The median OS was 17.8 (95% confidence interval (CI) 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best ORR and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child‒Pugh grade, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumor burden score, and combination with local therapy were independent prognostic factors for OS. A total of 100% and 57.9% of patients experienced all-grade and grade 3/4 treatment-emergent AEs, respectively. CONCLUSION: This real-world study of lenvatinib plus PD-1 inhibitor treatment demonstrated long survival and considerable ORRs and DCRs in uHCC patients in China. The tolerability of combination therapy was acceptable but must be monitored closely.

Co-expression of receptor tyrosine kinases and CD8 T-lymphocyte genes is associated with distinct prognoses, immune cell infiltration patterns and immunogenicity in cancers.

Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. Therefore, we systematically investigated the association between the RTKs and CD8 T-lymphocyte genes (CD8Ts) across cancers. We comprehensively evaluated alterations in RTK genes across cancers and examined the co-expression of RTKs and CD8Ts using a weighted gene co-expression network analysis. We found that RTKs exhibited extensive genetic alterations across cancers and were significantly related to the activity of cancer hallmark-related pathways. We identified co-expression between the RTKs and CD8Ts. The low co-expression score subtype was associated with significant better clinical benefits and was characterized by a hot immune microenvironment, including more infiltrating immune cells, higher chemokine expression, and stronger immunogenicity, such as the tumor mutation burden and neoantigens. Two immunotherapy cohorts confirmed that patients with low co-expression scores had an inflamed TME phenotype and significant therapeutic advantages. Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.

Efficacy of immune checkpoint inhibitors plus molecular targeted agents after the progression of lenvatinib for advanced hepatocellular carcinoma.

Background: Lenvatinib is a standard first-line systemic therapy in advanced hepatocellular carcinoma (aHCC) and is widely used in all lines. However, the efficacy and safety of immune checkpoint inhibitors (ICIs) plus molecular targeted agents (MTAs) after the progression of lenvatinib treatment are unclear. Objective: The aim of this study was to evaluate the anticancer effects of ICI plus MTA in patients with aHCC who progressed after lenvatinib. Methods: We retrospectively included aHCC patients treated with ICI plus MTA after the progression of lenvatinib from two medical centers. Participants who continued lenvatinib treatment were classified into the "ICI+Lenva" group, while the "ICI+Others" group included patients receiving other MTAs. The efficacy endpoints were progression-free survival (PFS), post-progression survival (PPS), overall survival (OS), and tumor response following RECIST v1.1. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. Results: In this study, 85 eligible aHCC patients were enrolled, including 58 in the ICI+Lenva group and 27 in the ICI+Others group. At a median follow-up time of 22.8 months, the median PPS and PFS were 14.0 (95% CI: 9.0-18.2) and 4.5 months (95% CI: 3.5-8.3), respectively. The objective response and disease control rates were 10.6% and 52.9%, respectively. No significant differences were observed in any of the efficacy endpoints between the two groups. Prolonged PPS was associated with Child-Pugh grade A, AFP < 400 IU/ml, and concomitant locoregional treatment. All patients experienced adverse events (AEs), but no fatal AEs were observed. Conclusion: ICI plus MTA in aHCC patients after the progression of lenvatinib presented high antitumor activity and safety. Patients could continue lenvatinib treatment and receive ICIs as well as locoregional treatment to achieve better OS.

Effects of Polypropylene Fibers on the Frost Resistance of Natural Sand Concrete and Machine-Made Sand Concrete.

In order to study the effect of polypropylene fibers on the frost resistance of natural sand and machine-made sand concrete, polypropylene fibers (PPF) of different volumes and lengths were mixed into natural sand and machine-made sand concrete, respectively. The freeze-thaw cycle test was carried out on polypropylene-fiber-impregnated natural sand concrete (PFNSC) and polypropylene-fiber-impregnated manufactured sand concrete (PFMSC), respectively, and the apparent structural changes before and after freezing and thawing were observed. Its strength damage was analyzed. A freeze-thaw damage model and a response surface model (RSM) were established used to analyze the antifreeze performance of PFMSC, and the effects of the fiber content, fiber length, and freeze-thaw times on the antifreeze performance of PFMSC were studied. The results show that with the increase in the number of freeze-thaw cycles, the apparent structures of the PFMSC gradually deteriorated, the strength decreased, and the degree of freeze-thaw damage increased. According to the strength damage model, the optimum volume of PPF for the PFNSC specimens is 1.2%, and the optimum volume of PPF for the PFMSC specimens is 1.0%. According to the prediction of RSM, PFNSC can maintain good antifreeze performance within 105 freeze-thaw cycles, and when the PPF length is 11.8 mm, the antifreeze performance of PFNSC reaches the maximum, its maximum compressive strength value is 33.8 MPa, and the split tensile strength value is 3.1 MPa; PFMSC can maintain a good antifreeze performance within 96 freeze-thaw cycles. When the length of PPF is 9.1 mm, the antifreeze performance of PFMSC reaches the maximum, its maximum compressive strength value is 45.8 MPa, and its split tensile strength value is 3.2 MPa. The predicted values are in good agreement with the measured values, and the model has high reliability.

Identification of an m6A-Related Long Noncoding RNA Risk Model for Predicting Prognosis and Directing Treatments in Patients With Colon Adenocarcinoma.

N6-methyladenosine (m6A) and lncRNAs have been implicated in the development of colon cancer, including tumorigenesis, migration, and invasion. However, the specific effect of m6A regulators on lncRNAs is not clear, and m6A-related lncRNAs may be new prognostic biomarkers and may help direct treatment and medication. We identified 29 prognostic m6A-related lncRNAs and constructed a risk model using 12 lncRNAs. The model was an independent prognostic factor and could accurately predict the prognosis. A stable and robust nomogram that combined the model and pathologic stage was constructed. A total of 2,424 differentially expressed genes (DEGs) were identified based on the model. Functional analysis of the DEGs showed that they were associated with tumor progression, helping investigate the underlying biological functions and signaling pathways of the risk model. In addition, the low-risk group based on the risk model had more sensitivity to afatinib, metformin, and GW.441756, and patients with low risk would more likely respond to immunotherapy. Moreover, patients with higher risk were more sensitive to olaparib, bexarotene, and doxorubicin.

Age, gender, geographic and clinical differences for gallstones in China: a nationwide study.

Background: The etiology of gallstones at different anatomical locations may be varied. However, it has not been well studied about the prevalence of gallstones by anatomical locations and their associated factors in China. Methods: We used the data set from preventive health screening centers covering all provinces in mainland China except for Tibet, and a total of 10,937,993 adults were included, who received abdominal ultrasonography in 2017. We analyzed the prevalence of gallstones classified by anatomical locations, including gallbladder (GB) stones, intrahepatic bile duct (IHD) stones, and extrahepatic bile duct (EHD) stones. Further, their associated factors were investigated using a logistic regression model with body mass index (BMI), fasting glucose, total triglyceride, and previous cholecystectomy, with covariates of age and sex. Results: The age- and gender-standardized prevalence (AGS-prevalence) of gallstone diseases was 5.13% (95% CI: 5.11-5.14%). GB, IHD, and EHD stones accounted for 76.3%, 24.3%, and 0.2% of all gallstone cases (concomitant cases were present). GB, IHD, and EHD gallstones presented different patterns by the age, gender, geographic and metabolic factors. Overall, the age-standardized prevalence was higher in women than that in men (5.41% vs. 4.85%, P<0.001). The gender standardized prevalence of all gallstone subtypes apparently increased with age (P<0.001), especially for GB stones from 1.05% (age 18-30) to 11.6% (age ≥70) (P<0.001). There was a marked geographic variation with AGS-prevalence ranging from 3.00% to 8.86% among different provinces. Noticeably, higher BMI, fasting glucose level, or total triglyceride level was associated with a higher prevalence of overall gallstones and GB stones (OR >1), but associated with a lower prevalence of IHD and EHD stones. Conclusions: The prevalence of gallstones in China largely varied in its anatomical location, demographic factors, geographic location, and metabolic factors, suggesting that the etiology of each subtype may be different. Further investigation should be conducted.

Differentially expressed liver exosome-related genes as candidate prognostic biomarkers for hepatocellular carcinoma.

Background: Exosomes are involved in cell-to-cell communication, neovascularization, cancer metastasis, and drug resistance, which all play an important role in the occurrence and progression of hepatocellular carcinoma (HCC). Because there are few mechanistic studies about the function of exosomes in HCC, the goals of this study were to identify exosome-related genes in HCC, to establish a reliable prognostic model for HCC, and to explore underlying mechanisms. Methods: The exoRBase and The Cancer Genome Atlas (TCGA) databases were used to analyze differentially expressed genes (DEGs). Cox regression and least absolute shrinkage and selection operator analyses were used to identify DEGs closely related to the overall survival of patients with HCC. An exosome-related prognostic model was then constructed in TCGA and validated in the International Cancer Genome Consortium database. A nomogram was developed to predict survival. CIBERSORT was used to estimate the abundance of different types of immune cells. Immunotherapy-related DEGs were used to predict the effect of immunotherapy. Results: Forty-eight exosome-related DEGs were obtained; of them, five [exportin 1 (XPO1), lysosomal thiol reductase (IFI30), F-box protein 16 (FBXO16), calmodulin 1 (CALM1), MORC family CW-type zinc finger 3 (MORC3)] were selected to construct a predictive model. Patients with HCC were then divided into low- and high-risk groups using the best cut-off value, as determined by the X-tile software. Prognosis was significantly poorer in the high-risk than in the low-risk group (P=0.009; hazard ratio =2.65). Features related to exosomes were found to positively regulate immune response. Further analysis showed a higher risk score was associated with higher expression of immune checkpoint molecules, including programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell Ig and ITIM domain (TIGIT), and indoleamine-2,3-dioxygenase 1 (IDO1). Conclusions: This study has identified a novel signature based on exosome-related genes that has potential as a prognostic biomarker for HCC. Our research provides an immunological perspective for the development of precision treatment for HCC.